Development of Novel Synthetic Alkaloids as Antimalarial Malaria still afflicts about half of the world population, causing more than a million deaths each year, mostly children. Most of the drugs currently used for malaria treatment are losing their effectiveness due to widespread emergence of drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line therapies against Plasmodium falciparum malaria are showing signs of resistance in wide areas of Southeast Asia. To address the fragility of malaria treatment measures, we have synthesized and screened a unique collection of >1,000 natural product-based small molecules for antiplasmodial activity using an unbiased cell-based assay. We have identified 5 novel antiplasmodial hits across novel alkaloid, pyrazoline, and macrocycle chemotypes. These compounds exhibit nanomolar potencies, and excellent selectivity in vitro. Furthermore, one of the alkaloid hits acts via a novel cellular mechanism, arresting parasite growth at the segmenter stage and blocking egress from erythrocytes. Based on these strong preliminary results, we hypothesize that these hits will be an excellent platform for hit- to-lead optimization to provide potent new antimalarials with mechanisms of action distinct from those of currently used drugs. To prove this hypothesis, we propose herein to develop one or more antimalarial lead compounds through a multidisciplinary collaboration between the labs of Debopam Chakrabarti (University of Central Florida) and Derek Tan (Memorial Sloan Kettering Cancer Center), comprising combined expertise in organic synthesis, medicinal chemistry, malaria cell biology, pharmacology, toxicology, and mouse models of malaria. (1) We will design and synthesize analogues of antiplasmodial hits to elucidate structure-activity and structure-property relationships. (2) We will evaluate analogues for in vitro antiplasmodial activity, cytotoxicity, cellular mechanisms of action, pharmacological properties, and in vivo pharmacokinetics, toxicology, and antimalarial efficacy. This is a highly significant endeavor, as we will develop novel lead compounds for malaria therapy with in vivo efficacy and defined cellular mechanisms of action for further preclinical and ultimately clinical development.